This is a research proposal designed to test the hypothesis; Can evidence for susceptibility gene be detected in bipolar (BP) disease through linkage analysis and/or association studies of pericentromeric DNA marker genotypes from multiplex Bp families. DNA samples from 22 multiplex BP families, consisting of approximately 400 informative persons (200 of whom are diagnosed as BPI, BPII with major depression, schizoaffective [SA], or recurrent unipolar [UP]), have been employed in a genomic search for BP disease genes. In examining peri-centromeric chromosome 18 DNA markers, eight of these pedigrees have shown positive lod scores, consistent with linkage. The affected pedigree member (APM) method and affected sibling pair method also yielded evidence suggesting that inheritance of disease was not independent of inheritance of marker alleles for five microsatellite loci. Funds are requested to study genetic variation of two 18p11.2 candidate genes, a G-protein alpha subunit gene (Golf) and an adrenocorticotropin (ACTH) receptor gene (MC-1). Pharmacologic and biochemical studies of BP disease and lithium suggest that these two genes are interesting candidate genes. Single stranded conformational polymorphism (SSAP) and denaturing gradient gel electrophoresis (DGGE) will be employed to screen the exons of these tow genes for variations. Detected variants will be sequenced to determine whether the variant results in altered amino acid sequences. BP individuals, in a haplotype relative risk association study, will be genotyped with variants giving rise to altered amino acid sequence to assess these two genes as possible susceptibility genes in BP disease.